Expert Critique

FROM THE ASCO Reading Room

Vinay Gupta, MDOncologySaint Luke's Cancer InstituteKansas City, MO

One of the under-recognized groups of lung cancer patients -- those without a clear and substantial tobacco exposure -- has been brought into the limelight after discovery of targetable molecular mutations. Clinically, this group of patients has had little or no smoking history, and they are more likely to be female and Asian.

In current clinical practice, molecular testing, at least for EGFR and ALK, is offered to all patients with adenocarcinomas. Given potential other actionable molecular makers in non-smokers, such as ROS, RET, MET, and HER2, performing a more comprehensive molecular analysis rather than just EGFR and ALK upfront may have significant therapeutic implications in terms of individualizing therapy.

The USPSTF guidelines and their endorsement by CMS have remarkably increased the awareness of lung cancer screening in smokers among primary care providers. Unfortunately, however, such awareness falls short for patients who do not have significant tobacco exposure. Risk stratification to identify high-risk patients needs to evolve to include other known risk factors such as family history; toxin exposure (radon, asbestos, radiation, metals); and medical comorbidities (pulmonary fibrosis, HIV).

Less data are available currently for predicting risk based on genomic analysis, but for the hopeful and optimistic among us, this is the next frontier.

Full Critique

The estimation that close to 90% of lung cancer cases can be tied to active smoking may be alarming, but it's not surprising. On the other hand, 20% of people in the U.S. who die from lung cancer annually did not smoke or use any other tobacco products.

"For patients who have never smoked, there are other risks and drivers of lung cancer, including environmental exposures like radon gas, asbestos, and secondhand smoke, as well as distinct genetic mutations in the tumors of never-smokers," explained Inga T. Lennes MD, of Massachusetts General Hospital in Boston. "We see certain molecular subtypes of lung cancer more frequently in nonsmokers, such as cancers with EGFR mutations and ALK rearrangements."

While public awareness campaigns and cessation programs have made headway in curbing smoking and the use of other tobacco products – in turn helping to cut lung cancer rates in users – the disease seems to be on the rise in people who have never partaken of tobacco.

A study presented at the 2015 World Conference on Lung Cancer found that the proportion of lung cancer patients who never smoked more than doubled from 2008 to 2014. In addition, both the percentage and absolute number of non-small cell lung cancer (NSCLC) cases in nonsmokers climbed during the study period, leading principal investigator Eric Lim, MB ChB, MD, of Royal Brompton Hospital in London, to point out that the increase was legitimate and not an artifact related to reductions in smoking prevalence.

What is the current profile of the lung cancer patients without a smoking history, and how should clinicians manage these patients?

As with the situation in smokers, adenocarcinoma is the predominant cancer type in nonsmokers, followed by carcinoid histology, Lim explained. Also in his study, women accounted for well over half of the never-smokers.

In terms of presentation, Lim reported in his study that more than half of the patients with a negative smoking history had nonspecific symptoms at diagnosis, such as cough, chest infection, and hemoptysis -- which begs the question, would patients with nonspecific symptoms benefit from CT-based lung cancer screening?

"That is a dilemma," Lim stated. "The symptoms [for both smokers and non-smokers] are non-specific; with smoking, one can readily identify it as a risk factor, but in non-smokers there are none."

Lim is the director of the BUPA Cromwell Lung Cancer Screening Programme, which currently follows CT-based lung cancer screening protocols, as set out by U.S. and European guidelines, in people with a smoking history. But screening all nonsmokers for potential lung cancer is not practical, so other tests -- ideally non-invasive ones or tests based on molecular screening -- are needed, he said.

Lennes recommended that any pulmonary symptoms, such as cough or infection, that do not resolve with treatment should be evaluated with diagnostic chest CT. "Additionally, patients with a radiographic diagnosis of infiltrate or pneumonia should have follow-up imaging to document resolution," she stated.

However, she also noted that the current data mainly support the use of lung screening in patients who meet screening criteria -- i.e., those with a smoking history. "Additional screening criteria, such as second-hand smoke exposure and a family history of lung cancer, are active areas of inquiry and research, and we hope to learn more about what groups of patients will benefit from screening," she said.

To that end, various studies have looked at the following:

How people with a family history of lung cancer – who have a two- to three-fold increased risk for developing the disease – tend to underestimate their risk level;

As for the factors that contribute to lung cancer rates in nonsmokers, research has been done, but definitive answers are still pending. For instance, a recent study that looked at small-cell lung cancer rates in never-smokers reported that residential radon exposure was higher than the levels recommended by the World Health Organization in these patients.

A pooled analysis of data in the risk of lung cancer in never smokers after exposure to secondhand smoke found "clear dose-response relationships consistent with a causal association ... between exposure to secondhand smoke from spousal, workplace, and social sources and the development of lung cancer among never-smokers."

Then there is the role genes play in lung cancer risk. An international analysis of heritability based on genome-wide association studies in 13 types of cancer found that only four "pairs of cancers," including bladder and lung, had marginally statistically significant correlations with genetics. However, the study authors noted that "the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures."

Finally, a Canadian study also reported that smokers with lung cancer carried different genetic mutations from non-smokers with lung cancer. In addition, lung cancer tumors in never-smokers had twice as many genetic abnormalities, particularly EGFR mutations, as those seen in current or former smokers.

Given that never-smokers are more likely to have the EGFR mutation, Lennes emphasized the importance of EGFR testing in all patients with metastatic or stage IV adenocarcinoma of the lung -- "as this change indicates that patients can and should be treated with an EGFR-directed therapy."

Lennes disclosed relationships with Blue Cross and Blue Shield of Massachusetts and with Kyruus.